Five things to know about folinic acid and autism
The FDA is relabeling folinic acid to treat a condition often associated with autism. How does it work?
As the Food and Drug Administration moves to make folinic acid an official treatment for a neurological condition associated with autism, parents want to know how it might help children with autism spectrum disorder.
Professors of pharmacy at Northeastern University talked about the promise and challenges of using folinic acid, also known as leucovorin, to treat autism symptoms in people with cerebral folate deficiency — and what to expect as the FDA approval process rolls out.
A vitamin essential for brain health
Folinic acid is a synthetic form of folate or B9, a vitamin found in leafy greens, beans and citrus foods that plays an important role in brain development, cell growth and DNA synthesis.
Folic acid, which is used in prenatal vitamins to prevent neural tube defects in babies, is also a synthetic form of folate but is used at much smaller dosages — micrograms instead of milligrams — says Carla Bouwmeester, a clinical professor of pharmacy and health systems sciences.
Folinic acid, known medically as leucovorin, has been used on a prescription basis for decades to treat side effects from chemotherapy, particularly toxicity from a drug called methotrexate, says Joseph Elijah, an assistant professor of pharmacy and health systems sciences.
For the past 20 or so years, it also has been used off-label to treat cerebral folate deficiency or CFD, a neurological condition in which the brain has insufficient folate.
“What’s new is it would be a labeled indication” for CFD with the expected FDA approval, Bouwmeester says.
Autism association with CFD
Discovered more than 20 years ago, CFD was quickly associated with autism spectrum disorder, especially since some symptoms such as speech and motor delays overlap.
Typically, children with CFD are found to have folate receptor autoantibodies known as FRAAs that block folate from being transported across the blood-brain barrier.
It turns out that children with autism spectrum disorder are 19-fold more likely to be positive for these autoantibodies than typically developing children without an autistic sibling, according to a study of leucovorin treatment.
Promising but not a ‘miracle cure’
There have been several small studies and a randomized controlled trial that show high doses of leucovorin improve verbal communication and other behaviors in autistic children, especially in those who have tested positive for folate receptor autoantibodies, Elijah says.
“The results are promising,” he says, but more data is needed.
“It’s not a miracle cure,” Bouwmeester says.
“It’s not being approved to treat autism,” Bouwmeester says. “It’s being approved to treat cerebral folate deficiency.”
“This medication is essentially providing the folate in the brain for people who are not able to process that normally,” she says.
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What’s next
In going through the process of expanding the leucovorin label to cover CFD, the FDA is eschewing large-scale clinical trials and relying instead on a systemic analysis of literature published between 2009 and 2024, including published case reports.
“Children are suffering and deserve access to potential treatments that have shown promise,” says FDA Commissioner Dr. Marty Makary.
Elijah says more studies are needed to determine the length of treatment time and optimum dosing.
“There are unanswered questions right now,” he says.
In the past, researchers may have used larger doses than necessary to establish effectiveness, knowing that excess vitamin B likely would be eliminated harmlessly through urine, Elijah says.
“Leucovorin is typically well tolerated, but every medication also has side effects,” Bouwmeester says.
She says it’s important to look at drug interactions, especially since leucovorin can decrease the effectiveness of seizure medications that are sometimes prescribed to children with autism spectrum disorder or cerebral folate deficiency.
Enough to go around
Another issue is making sure there remains a large enough supply of folinic acid to fill the demand for prescriptions, Elijah says.
Leucovorin is a generic, relatively inexpensive drug.
“We have to be mindful if we were to start using it in large quantities” of diverting the medication from oncology patients and others who need it, Elijah says.
Not only does leucovorin offer protection for people with blood and other cancers who are receiving high-dose methotrexate, “it improves the effectiveness of colorectal cancer therapy,” he says.
We don’t want to potentially help a subset of people by harming another,” Elijah says.
